EP3585785B1 - Process for the preparation of methyl 4-[(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1h-1,2,4-triazol-1-yl)carbonyl)sulfamoyl]-5-methylthiophene-3-carboxylate - Google Patents

Description

The invention relates to an improved process for the preparation of methyl 4 - [(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1 H -1,2,4-triazole-1-yl) carbonyl) sulfamoyl ] -5-methylthiophene-3-carboxylate (known under the common name "Thiencarbazone-methyl").

The herbicidal effect of substituted thien-3-yl-sulfonylaminocarbonyl-triazolinones is from the document DE 199 33 260 A1 and from document WO 01/05788 A1 in which the priority of the DE 199 33 260 A1 is claimed is known.

Selected substituted thien-3-yl-sulfonylamino-carbonyltriazolinones, such as thiencarbazone-methyl, have a particularly good herbicidal effect.

Because of the good effect, the improvement of the processes for the production of the aforementioned herbicides, also with regard to the environmental compatibility of the production, has become a constant endeavor in chemical research.

document DE 19933260 A1 discloses, in addition to four other process alternatives, with alternative (c) a process for the preparation of substituted thien-3-yl-sulfonylaminocarbonyl-triazolinones by reacting sulfonyl isocyanates with 5-methoxy-4-methyl-2,4-dihydro-3H-1 , 2,4-triazol-3-one. In this alternative process mentioned above, the possibility of reacting substituted thiophene-3-sulfonic acid chlorides with substituted triazolinones and metal (thio) cyanates, optionally in the presence of a reaction auxiliary, and optionally in the presence of a diluent, is merely outlined by a formula scheme (cf. DE 19933260 A1 , Page 7), but not proven by an example.

In connection with the process alternatives (a) to (e), in DE 19933260 A1 optional reaction auxiliaries disclosed. These relate to acid binders which can usually be used for such reactions. The on page 9 of DE 19933260 A1 mentioned selection also includes potassium tert-butoxide and basic nitrogen compounds such as amines including tributylamine and pyridines such as 2-methylpyridines, 3-methylpyridines, 5-ethyl-2-methylpyridines, 2,6-dimethylpyridines.

In contrast, imidazoles are used in DE 19933260 A1 not mentioned as a reaction aid.

In document DE 10 2004 063192 A1 is used to prepare the sulfonyl isocyanate, using the in DE 19933260 A1 disclosed process alternative (ie preparation of Thiencarbazone-methyl by reaction of sulfonyl isocyanate with 5-methoxy-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one) proposed a process starting from sulfonamide and phosgene .

However, this is in DE 10 2004 063192 A1 disclosed methods, due to the use of phosgene, which is classified as highly toxic, dangerous and thus complex and expensive.

Against this background, the object of the invention is to provide an improved process for the preparation of substituted thien-3yl-sulfonylamino-carbonyltriazolinones, in particular thiencarbazone-methyl, ie the compound of the formula (I), the improved process being the preparation of the target compound thiencarbazone -methyl should enable high purity and yield.

durch Umsetzung der Verbindung der Formel (II)

mit einem Metallcyanat der Formel (III)

        MeOCN     (III)

, worin Me für Li, Na, K oder, Cs steht mit der Verbindung der Formel (IV)

, wobei die Umsetzung in Gegenwart eines Imidazols der Formel (V)

, worin der Rest R1 für ein unsubstitutiertes (C₁-C₁₂)-Alkyl oder für ein unsubstitutiertes Benzyl steht, erfolgt.The object is achieved by the process according to claim 1 for the preparation of the compound of the formula (I)

by reacting the compound of formula (II)

with a metal cyanate of the formula (III)

MeOCN (III)

where Me stands for Li, Na, K or, Cs with the compound of formula (IV)

, where the reaction in the presence of an imidazole of the formula (V)

, in which the radical R1 is an unsubstituted (C ₁ -C ₁₂ ) -alkyl or an unsubstituted benzyl.

Surprisingly, it was found in connection with the process according to the invention that the use of alkyl-substituted imidazoles, in particular of N-alkylimidazoles, the production of substituted thien-3yl-sulfonylaminocarbonyl-triazolinones, in particular the production of methyl 4 - [(4,5-dihydro-3 Methoxy-4-methyl-5-oxo-1 H -1,2,4-triazole-1-yl) carbonyl) sulfamoyl] -5-methylthiophenes-3-carboxylate (thiencarbazone-methyl) in a particularly high purity and yield enables.

The invention is thus based on the finding that the compound of the formula (I) thiencarbazone-methyl under certain conditions, namely in the presence of an imidazole base substituted in the 1-position or in the presence of a base mixture which has a 1-position substituted imidazole base (N-alkylimidazole) contains, can be prepared directly from 4-methoxycarbonyl-2-methyl-thiophene-3-sulfonic acid chloride (compound of formula (II)) with a high purity and yield.

Reaction scheme:

The above reaction scheme shows that when the reaction is carried out as a one-pot synthesis, a 4-component system is present at the start of the reaction.

In the case of a two-stage reaction, the starting material 5-methoxy-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one of the formula (IV) is only added after the sulfonyl isocyanate has been formed from compounds of the formulas ( II) and (III) are added to the mixture in the presence of an N-alkylimidazole of the formula (V).

The synthesis of the starting materials, ie the synthesis of the compounds of the formulas (II) and (IV) in the aforementioned reaction scheme, is in DE 19933260 A1 disclosed. The compounds of the formula (III) and (V) are commercially available.

It is assumed that the imidazoles (N-alkylimidazoles) substituted in the 1-position by an alkyl radical act particularly well as activators (= activating agents) and / or stabilizers in the formation of the sulfonyl isocyanate in the formation of the sulfonyl isocyanate.

The core of the present invention, however, relates to the surprising finding that the metal cyanate with the sulfonyl group of the respective thiophene compound (in the above scheme with the methyl 4- (chlorosulfonyl) -5-methylthiophene-3-carboxylate of the formula (II)) in the presence of an N-alkylimidazole of the formula (V) reacts selectively to form a sulfonyl isocyanate, and that the substituted thien-3yl-sulfonylamino-carbonyltriazolinone (in the above reaction scheme, the target compound thiencarbazone-methyl (I)) is then formed from this.

The unexpected selectivity of the reaction shown in the scheme consists in the fact that the triazolinone (IV) only reacts further with the sulfonyl isocyanate to form thiencarbazone-methyl after formation of the sulfonyl isocyanate.

In addition, with regard to the use of a metal cyanate in a chemical reaction, it should be considered in general that metal cyanates are strong bases (sodium cyanate (NaOCN), for example, has a pH of 10). At the same time, metal cyanates act as O nucleophiles.

In the presence of an N-alkylimidazole, in particular in the presence of N-methylimidazole, the O-nucleophilicity of the metal cyanates used according to the invention surprisingly has no effect on the course of the present reaction, i.e. its yield and selectivity.

This does not apply to the use of other basic nitrogen compounds such as pyridines, picolines or 4- (dimethylamino) pyridine (DMAP), which are to be regarded as classic activators for, for example, carboxylic acid halides. The same applies to the use of inorganic bases such as K ₂ CO ₃ or potassium tert-butoxide (KOtBut), which have also proven to be unsuitable.

It was demonstrated by example that the thiencarbazone-methyl yield when using the process according to the invention is unexpectedly high compared to carrying out the reaction using other alternative basic nitrogen compounds.

It is preferred to carry out the process according to the invention in the presence of an imidazole of the formula (V) in which the radical R _{1 is} an unsubstituted (C ₁ -C ₆ ) -alkyl or an unsubstituted benzyl. Carrying out the process in the presence of an imidazole of the formula (V) in which the radical R _{1 is} a substituted (C ₁ -C ₆ ) -alkyl or a substituted benzyl is not preferred, but is likewise within the scope of the invention.

It is particularly preferred to carry out the process according to the invention in the presence of an imidazole of the formula (V) in which the radical R _{1 is} an unsubstituted (C ₁ -C ₄ ) -alkyl. Unbranched (C ₁ -C ₄ ) -alkyl, ie methyl, ethyl, n-propyl or n-butyl for R _1, are very particularly preferred.

It is most preferred to carry out the process according to the invention in the presence of N-methylimidazole (NMI), ie when. the radical R ₁ in formula (V) represents methyl.

To prepare the compound of the formula (I) in the process according to the invention, the reagents are preferably used in equimolar amounts or in excess.

In general, 1 to 2.5 mol, preferably 1 to 2 mol, particularly preferably 1 to 1.8 mol, of the metal cyanate of the formula MeOCN (III) are used per mole of sulfonic acid chloride, ie the compound of the formula (II). However, the use of relatively large excesses of the compound of the formula (III) is also within the scope of the invention.

In a preferred embodiment, Me in compounds of the formula MeOCN (III) stands for Na or for K. The most preferred metal cyanate in the process according to the invention is NaOCN. Furthermore, per mole of sulfonic acid chloride, ie of the compound of the formula (IV) (5-methoxy-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one), there are also 1 to 2 Mol, preferably 1 to 1.5 mol, particularly preferably 1 to 1.1 mol.

However, the use of relatively large excesses of the compound of the formula (IV) is also within the scope of the invention.

The process is carried out in an organic solvent, with non-polar and polar solvents being suitable.

Suitable non-polar solvents are toluene, chlorobenzene, xylene, methyl tert-butyl ether, methyl isopropyl ether, ethyl acetate, isopropyl acetate and butyl acetate.

Particularly preferred polar solvents are selected from the group consisting of acetonitrile, butyronitrile, tetrahydrofuran (THF), methyl-THF, dimethoxyethane, sulfolane, dimethylformamide and dimethylacetamide.

Most preferred solvents are acetonitrile and THF.

Mixtures of different solvents can also be used.

The reactants are preferably reacted in a temperature range from 20 ° to 110 ° over a period (reaction time, reaction time) of 3 hours to 24 hours.

The reaction of the starting materials in a temperature range from 30 ° to 90 ° is very particularly preferred. Most preferably, the reactants are reacted in a temperature range from 50 ° to 80 °.

, worin der Rest R₁ für ein unsubstitutiertes (C₁-C₁₂)-Alkyl oder für ein unsubstitutiertes Benzyl steht, zur Herstellung der Verbindung der Formel (I)

Another aspect of the invention relates to the use of an imidazole of the formula (V)

, in which the radical R _{1 is} an unsubstituted (C ₁ -C ₁₂ ) -alkyl or an unsubstituted benzyl, for the preparation of the compound of the formula (I)

The use of an imidazole of the formula (V) in which R _{1 is} an unsubstituted (C ₁ -C ₄ ) -alkyl is preferred.

It is particularly preferred to use an imidazole of the formula (V) in which R _{1 is} an unbranched and unsubstituted (C ₁ -C ₄ ) -alkyl, ie, methyl, ethyl, n-propyl or n-butyl.

Most preferred is the use of an imidazole of the formula (V) in which R _{1 is} methyl.

EXAMPLES:

The production process according to the invention can be carried out as a one-pot process or as a two-stage reaction.

In the one-pot process, all chemicals are mixed in an organic solvent and then heated while stirring. In order to better control the exothermicity of the reaction, it is also advisable to use the reagents of the formula (III), (IV) and (V) in e.g. B. to submit acetonitrile in order to then slowly add the sulfonyl chloride of the formula (II) as a solution at the reaction temperature.

During the reaction, the active ingredient or its salt precipitates out of the reaction mixture and can simply be filtered off.

It is particularly advantageous to add an inorganic base such as LiOH, K ₂ CO ₃ , NaHCO ₃ , NaOH, Na ₂ CO ₃ , CaCO ₃ or KOH to the mixture at the end of the reaction in order to convert the active ingredient as insoluble Li, Na, Isolate K or Ca salt. The use of NaHCO ₃ is preferred. In this way, the active ingredient can be isolated with a very high degree of purity.

The amount of base to be used depends on how much metal cyanate is used when carrying out the reaction. If only 1 equivalent (eq) of NaOCN is used, 1 eq. Of base is then required to completely convert the active ingredient into the salt (example 1). If you set for example 2 eq of the metal cyanate, for example 2 eq NaOCN, to carry out the reaction, no additional base is necessary (cf. Example 3).

Treatment of the salt with an acid (eg HCl, H ₂ SO ₄ ) releases the active ingredient and isolates it after filtration.

It is also possible to first react the compound of the formula (II) with MeOCN in the presence of the compound of the formula (V) in order to prepare the sulfonyl isocyanate of the formula (VI). In a second step, the sulfonyl isocyanate is then reacted with 5-methoxy-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one of the formula (IV), if necessary without prior isolation.

The analysis, identification and determination of the content of sulfonyl isocyanate after step 1 is based on the derivatization with methanol to give the corresponding carbamate of the formula (VII).

If necessary, the isocyanate can be isolated and purified by distillation in vacuo. TABLE 1 Tabular comparison of the yields based on LC analysis when using different reaction auxiliaries for the preparation of methyl 4 - [(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1 H -1,2,4-triazole-1 -yl) carbonyl) sulfamoyl] -5-methylthiophenes-3-carboxylate (thiencarbazone-methyl), in acetonitrile, NaOCN 2 eq. Comparison No. Amount of activator / mole eq Time (hrs) / T ° C Target product LC, area% 1 2-methylpyridine / 1 12/80 26th 2 3-methylpyridine / 1 12/80 36 3 3-methylpyridine / 0.1 12/80 25th 4th 2-methyl-5-ethylpyridine / 1 12/80 27 5 2-methyl-5-ethylpyridine / 5 12/80 29 6 p-dimethylaminopyridine / 0.5 12/80 34 7th 2,6-dimethylpyridine / 1 12 (80) 37 8th Tributylamine / 1 12 (60) 5 9 KOtBut / 1 12 (80) 0 10 N-butylimidazole / 1 12 (80) 84 11 N-methylimidazole / 1 12 (80) 92 12th N-methylimidazole / 0.8 12 (80) 91

The table above shows that the thiencarbazone-methyl yield when using the method according to the invention when using N-butylimidazole and N-methylimidazole is unexpectedly high compared to other nitrogen bases. In contrast, when comparing the nitrogen base tributylamine, the target product thiencarbazone-methyl, which can be detected by liquid chromatography (LC), is in a low% range. If the acid binding agent potassium tert-butylate (KOtBut) is used, product verification is not possible at all.

SYNTHESIS EXAMPLES example 1 Methyl 4 - [(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1 H -1,2,4-triazole-1-yl) carbonyl) sulfamoyl] -5-methylthiophene-3-carboxylate (One-pot process)

25.4 g of methyl 4- (chlorosulfonyl) -5-methylthiophene-3-carboxylate, 6.5 g NaOCN, 12.9 g N-methylimidazole and 12.9 g 5-methoxy-4-methyl-2,4-dihydro -3H-1,2,4-triazol-3-one is placed in 200 ml of acetonitrile and heated to 70.degree. The mixture was heated at this temperature for 12 hours with stirring and cooled to 20 ° C.

8.5 g of NaHCO _{3 were} added to the mixture and the suspension was stirred at 20 ° C. for 3 hours. The precipitate was filtered off, washed with 50 ml of 10% HCl and 100 ml of water and dried at 50.degree. 31.6 g was obtained des_Methyl 4 - [(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1 H -1,2,4-triazole-1-yl) carbonyl) sulfamoyl] -5 methylthiophene-3-carboxylate, 80% of theory with a melting point of 201 ° C, and a purity of 99%.

Example 2 Methyl 4 - [(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1 H -1,2,4-triazole-1-yl) carbonyl) sulfamoyl] -5-methylthiophene-3-carboxylate (One-pot process)

25.4 g. of methyl 4- (chlorosulfonyl) -5-methylthiophene-3-carboxylate, 11.7 g NaOCN, 8.2 g N-methylimidazole and 12.9 g 5-methoxy-4-methyl-2,4-dihydro-3H -1,2,4-triazol-3-one is placed in 220 ml of acetonitrile and heated to 70.degree. The mixture was heated with stirring at this temperature for 18 hours and cooled to 20 ° C. 1.7 g of NaHCO _{3 were} added to the mixture and the suspension was stirred at 20 ° C. for 2 hours. The reaction mixture was heated to 60 ° C., the precipitate was filtered off and washed with 50 ml of acetonitrile. The precipitate was then washed with 70 ml of 20% H ₂ SO ₄ , 100 ml of hot (70 ° C.) water and 50 ml of acetone and dried at 50 ° C. This gave 31.4 g of methyl 4 - [(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1 H -1,2,4-triazole-1-yl) carbonyl) sulfamoyl] - 5-methylthiophen-3-carboxylate, 79% of theory with a purity of 98%.

Example 3 Methyl 4 - [(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1 H -1,2,4-triazole-1-yl) carbonyl) sulfamoyl] -5-methylthiophene-3-carboxylate (One-pot process)

25.4 g of methyl 4- (chlorosulfonyl) -5-methylthiophene-3-carboxylate, 13 g NaOCN, 12.9 g N-methylimidazole and 12.9 g 5-methoxy-4-methyl-2,4-dihydro-3H -1,2,4-triazol-3-one is in 200 ml Submitted acetonitrile and heated to 70 ° C. The mixture was heated at this temperature for 12 hours with stirring and cooled to 20 ° C.

The precipitate was filtered off, washed with 50 ml of 10% HCl and 100 ml of water and dried at 50.degree. This gave 33.6 g of methyl 4 - [(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1 H -1,2,4-triazole-1-yl) carbonyl) sulfamoyl] - 5-methylthiophen-3-carboxylate, 84.4% of theory with a purity of 98%.

Example 4 Methyl 4 - [(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1 H -1,2,4-triazole-1-yl) carbonyl) sulfamoyl] -5-methylthiophene-3-carboxylate (Two-step process)

25.4 g of methyl 4- (chlorosulfonyl) -5-methylthiophene-3-carboxylate, 6.5 g of NaOCN, 12.9 g of N-methylimidazole were placed in 150 ml of acetonitrile and the mixture was heated at 50 ° C. for 4 hours. The suspension was filtered through a glass frit under argon and 12.5 g of 5-methoxy-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one were added to the filtrate. The mixture was then heated at 70 ° C. for 8 hours and cooled to 20 ° C.

8 g of NaHCO ₃ and 1 ml of water were added to the mixture and the suspension was stirred for 3 hours. The precipitate was filtered off, washed with 50 ml of 10% HCl and 100 ml of water and dried at 50.degree. This gave 29.6 g of methyl 4 - [(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1 H -1,2,4-triazole-1-yl) carbonyl) sulfamoyl] - 5-methylthiophene-3-carboxylate 75.6% of theory with a melting point of 201 ° C. and a purity of> 99%.

Example 5 Methyl 4 - [(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1 H -1,2,4-triazole-1-yl) carbonyl) sulfamoyl] -5-methylthiophene-3-carboxylate (Two-step process)

25.4 g of methyl 4- (chlorosulfonyl) -5-methylthiophene-3-carboxylate, 11.7 g of NaOCN, 12.3 g of N-methylimidazole were placed in 150 ml of acetonitrile and the mixture was heated at 50 ° C. for 4 hours. The suspension was filtered through a glass frit under argon and 12.5 g of 5-methoxy-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one were added to the filtrate. The mixture was then heated at 70 ° C. for 12 hours and cooled to 20 ° C.

1.7 g of NaHCO ₃ and 1 ml of water were added to the mixture and the suspension was stirred for 3 hours. The precipitate was filtered off, washed with 50 ml of 10% HCl and 100 ml of hot water and dried at 50.degree. This gave 30.5 g of methyl 4 - [(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1 H -1,2,4-triazole-1-yl) carbonyl) sulfamoyl] - 5-methylthiophen-3-carboxylate 77% of theory with a purity of 98%.

Example 6 Methyl 4- (methoxycarbonylsulfamoyl) -5-methyl-thiophene-3-carboxylate

25.4 g of methyl 4- (chlorosulfonyl) -5-methylthiophen-3-carboxylate, 6.5 g of NaOCN, 12.9 g of N-methylimidazole were placed in 150 ml of acetonitrile and the mixture was heated at 50 ° C. for 4 hours. The suspension was filtered through a glass frit under argon, and 30 ml of methanol were added. After 1 hour, the solution was completely concentrated and the precipitate was washed with water and dried. 24 g of methyl 4- (methoxycarbonylsulfamoyl) -5-methyl-thiophene-3-carboxylate were obtained ( ¹ H NMR: (d ⁶ DMSO) 2.72 (s), 3.62 (s), 3.79 (s) , 8.01 (s), 12.01 (s) ppm).

Claims (15)

1. Method for preparing the compound of the formula (I)

   

   by reacting the compound of the formula (II)

   

   with a metal cyanate of the formula (III)
   
           MeOCN     (III)
   
   where Me is Li, Na, K or Cs
   and
   with the compound of the formula (IV)

   

   wherein the reaction is carried out in the presence of an imidazole of the formula (V)

   

   where the radical R₁ is an unsubstituted (C₁-C₁₂) -alkyl or an unsubstituted benzyl.
2. Method for preparing compounds of the formula (I) according to Claim 1, characterized in that R₁ is an unsubstituted (C₁-C₆)-alkyl or an unsubstituted benzyl.
3. Method for preparing compounds of the formula (I) according to Claim 2, characterized in that R₁ is an unsubstituted (C₁-C₄)-alkyl.
4. Method for preparing compounds of the formula (I) according to Claim 3, characterized in that R₁ is methyl, ethyl, n-propyl or n-butyl.
5. Method for preparing compounds of the formula (I) according to Claim 4, characterized in that R₁ is methyl.
6. Method for preparing compounds of the formula (I) according to any of Claims 1 to 5, characterized in that Me in compounds of the formula MeOCN (III) is Na or K.
7. Method for preparing compounds of the formula (I) according to any of Claims 1 to 6, characterized in that the reaction is carried out in a polar solvent selected from the group consisting of acetonitrile, butyronitrile, tetrahydrofuran (THF), methyl-THF, dimethoxyethane, sulfolane, dimethylformamide and dimethylacetamide.
8. Method for preparing compounds of the formula (I) according to any of Claims 1 to 6, characterized in that the reaction is carried out in a solvent mixture consisting of acetonitrile and THF.
9. Method for preparing compounds of the formula (I) according to any of Claims 1 to 8, characterized in that the reaction of the reactants is conducted

   - in a temperature range of 20° to 110° and

   - in a reaction time of 3 hours to 24 hours.
10. Method for preparing compounds of the formula (I) according to Claim 9, characterized in that the reaction of the reactants is conducted in a temperature range of 30° to 90°.
11. Method for preparing compounds of the formula (I) according to Claim 10, characterized in that the reaction of the reactants is conducted in a temperature range of 50° to 80°.
12. Use of an imidazole of the formula (V)

    

    where the radical R₁ is an unsubstituted (C₁-C₁₂) -alkyl or an unsubstituted benzyl, for a method for preparing the compound of the formula (I)

    

    according to any of Claims 1 to 9.
13. Use of an imidazole of the formula (V) according to Claim 12, characterized in that R₁ is an unsubstituted (C₁-C₄)-alkyl.
14. Use of an imidazole of the formula (V) according to Claim 13, characterized in that R₁ is methyl, ethyl, n-propyl or n-butyl.
15. Use of an imidazole of the formula (V) according to Claim 14, characterized in that R₁ is methyl.